Methylphenidate, known commonly as Ritalin, is a central nervous system stimulant used mainly for ADHD, but also for narcolepsy. ADHD is caused by an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD-4), and/or the D2 receptor gene. It has also been found to affect the alpha-2A adrenergic receptor in the prefrontal cortex. This abnormality makes it harder for dopamine and norepinephrine to bind to the receptors. These receptors regulate attention, movement, and impulsivity so a defeciency in the regulation of those systems causes ADHD. Methylphenidate blocks the reuptake transporters of both dopamine and norepinephrine which prolongs their duration in the synapse so that they can bind more readily to the receptors. Since it works in the brain Methylphenidate crosses the blood brain barrier through diffusion. Dopamine is synthized in the ventral tegmental area of the brain from tyrosine being synthesized into L-dopa by the enzyme Tyrosine 3-monooxygenase . L-Dopa is then syntheized into dopamine with the enzyme aromatic-L-amino-acid decarboxylase. Dopamine then travels to the prefrontal cortex where it is released into the synapse when the neuron is stimulated and fires. Methylphenidate binds to the sodium-dependent dopamine transporter which prevents dopamine from re-entering the presynaptic neuron. The dopamine then binds to Dopamine D4 receptors on the postsynaptic membrane. The dopamine D4 receptor activates the Gi protein cascade which inhibits adenylate cyclase. This prevents adenylate cyclase from catalyzing ATP into cAMP. The low concentration of cAMP is unable to activate protein kinase A which prevents or lowers neuronal excitability. It is unknown how exactly this helps with ADHD, but it is speculated to help by regulating attention, movement, and impulsivity to a greater degree. Other dopamine and norepinephrine receptors are likely also involved, but the main receptors complicit in ADHD are the dopamine D4 receptor and the alpha-2A adrenergic receptor. This helps people with ADHD to sustain attention and working memory.

Methylphenidate Dopamine Reuptake Inhibitor Pathway References